Uterine leiomyoma By the end of their reproductive years, over 50% of women in the United States develop uterine fibroids, making the condition the most prevalent reproductive disorder of women. Despite their prevalence, the condition remains poorly understood. One prominent feature of uterine fibroids is that cells within the tumors produce a disordered and excessive extracellular matrix (ECM). Previously, we have examined the ECM and characteristics of the cells that produce this excessive and fibrotic ECM and have found that mechanical signaling (a method of cell communication and activation) was altered in cells within a fibroid. In the past year we have found that cells that comprise a fibroid have impaired responses (decreased) to mechanical stimuli. Additionally, we completed a collaborative clinical trial led by Drs. Wood, Stratton and Venkatesan of MRI-guided high frequency ultrasound (HIFU) for the non-surgical treatment of uterine fibroids. In the coming year we plan to begin a second study with HIFU for the non-surgical treatment of uterine fibroids. Chronic Pelvic Pain and Endometriosis We have continued to investigate the association of chronic pelvic pain and endometriosis. This ongoing clinical study led by Dr. Stratton examines the relationship between chronic pelvic pain and endometriosis in three cohorts of women: women with chronic pain and endometriosis, those with chronic pelvic pain but no evidence of endometriosis, and healthy volunteers. Chronic pelvic pain is associated with endometriosis, but we have found that the location of superficial lesions does not correlate with pain location in a cohort of women with endometriosis. We also have found that two thirds of women with chronic pelvic pain have migraine headaches, a finding independent of endometriosis. These findings suggest that chronic pelvic pain associated with endometriosis is likely the result of central nervous system sensitization and myofascial dysfunction. Assessment and preservation of ovarian function in women and young girls undergoing cancer treatment Because of improved survival and effective chemotherapy for cancers, many young girls and women now are able to survive cancer, but find that reproductive function is impaired. In the past year we have completed animal and clinical investigations with plans to continue additional studies in a pediatric clinical populations and additional animal studies to examine potential mechanism(s) for preservation of primordial follicles after exposure to alkylating agents. We will also continue our study of diminished ovarian reserve in infertility patients. In the past year we reported animal data that suggested GnRH analogues preserve primordial follicles after exposure to the chemotherapy agent, cyclophosphamide. Results suggested that this may be due to a decrease in apoptosis (programmed cell death). In the coming year, we plan to investigate possible mechanism(s) involved. We also plan to begin a clinical study to examine new biomarkers of ovarian reserve in this patient population. Infertility and reproductive health disparities Our unit has continued to conduct studies of infertility and reproductive health disparities. Dr. Armstrong helped to established a Special Interest Group and national research network on the topic of Health Disparities. Investigators in the branch helped to arrange the a new abstract session at the Annual Meeting of the American Society of Reproductive Medicine on this reproductive health disparities. In the past year, Dr. Armstrong also led an NICHD-hosted conference on Health Disparities. In the coming year, the plans are to initiate a project to examine ethnic and racial differences in exposure to environmental reproductive toxins. Role of BRX (also known as AKAP13) in cardiac development, immune function and reproduction Our previous studies of the gene BRX (AKAP13), cloned by our group, indicated that this large Rho-GEF protooncoprotein was involved in estrogen and glucocorticoid receptor activation. We previously found that the BRX gene product coordinates G-sub-alpha-s and Rho signaling with an essential transcription program in developing cardiomyocytes in mice, involving myocyte enhancer factor 2 C (MEF2C). Mice with two defective copies of the AKAP13 gene (knockout) died in utero. In the past year we have made progress on development of a conditional gene targeting strategy using the Cre-Lox system in mice. Plans are to examine the phenotypes of the conditionally-targeted offspring. In addition, in the coming year we will examine the phenotypes of mice heterozygous for the AKAP13 null allele to determine whether these mice may have subtle abnormalities in estrogen or glucocorticoid signaling.